Insights on the regulation of the MLL/SET1 family histone methyltransferases
Introduction
Histone lysine methylation is a major post-translational modification (PTM) in eukaryotes. It occurs on the ε-amino group in three discrete states of mono-, di-, and tri-methylation. Since the first histone lysine methyltransferase (KMT or HMT) was discovered twenty years ago [1], over 60 putative or predicted enzymes have been identified [2]. Among well-characterized KMTs, the highly conserved mixed lineage leukemia (MLL or KMT2) family of proteins is responsible for deposition of the majority of histone 3 lysine 4 (H3K4) methylation in eukaryotes. Complexity of the H3K4 HMTs increases as eukaryotes evolved from single cell organisms to mammals, concomitant with increasing demands for spatial and temporal gene regulation. In yeast, ySET1 (Su(Var)3–9, Enhancer of Zeste, Trithorax), an MLL homolog, is responsible for all H3K4 methylation [[3], [4], [5]]. In Drosophila melanogaster, there are three MLL family enzymes, TRX, TRR, and dSET1, responsible for global H3K4 methylation [6,7]. Each of the three genes (i.e. TRX, TRR and dSET1) are duplicated in mammals, giving rise to MLL1 and MLL2 (KMT2A and 2B), MLL3 and MLL4 (KMT2C and 2D), and SET1A and SET1B (KMT2F and 2G), respectively. Despite general conservation of the catalytic SET domain, each MLL/SET1 protein has non-redundant functions in development and is subject to distinct regulations [6]. Recent cryo-EM structures have revealed how the MLL1, MLL3 and ySET1 complexes bind to the nucleosome core particle (NCP) [[8], [9], [10], [11]]. These studies shed light on distinct features of these MLL complexes on chromatin that may have implications for their respective regulation. Here we will focus on these exciting new discoveries and discuss how chromatin binding by the MLL family proteins is regulated in eukaryotes.
Section snippets
Regulation of the MLL methyltransferase activity on the NCPs
2a. MLL Family Enzymes Reside in a Conserved Core Complex.
The MLL/SET1 family enzymes are large proteins with multiple functional domains containing substantial stretches of disordered regions [12,13]. While they share a highly conserved C-terminal SET domain that confers H3K4 methylation [14], they also have subclass specific domains such as the CxxC and bromodomain for KMT2A/2B, the PHD domains for KMT2A-D, and the RRM domain for KMT2F/G. Biochemical studies show that the catalytic SET
Multi-Valent Chromatin Interactions for MLL1
While structural and biochemical studies show extensive interactions between the MLL/SET1 core complex and the NCP, the MLL/SET1 family enzymes also contain multiple other chromatin-interacting domains that are capable of recognizing specific patterns of histone and DNA modifications. These interactions may contribute to specific distribution of H3K4 methylation at transcriptionally-active gene promoters and distal regulatory enhancers [47] as well as colocalization of H3K4 methylation with
Closing remarks
Spatial and temporal regulation of gene expression is crucial for normal development and proper cellular response to environmental cues. The MLL/SET1 family proteins, through histone H3K4 methylation, play essential roles in regulating specific gene programs in cells. As revealed in the recent cryo-EM structures of the MLL1-NCP complex [8,10], stabilization of the MLL1 complex on chromatin likely enhances the higher H3K4 methylation states, which is pivotal for transcription activation. These
Funding
This work is supported by Michigan Institute for Clinical and Health Research (MICHR) Postdoctoral Translational Scholar Program (PTSP) Fellowship to L.S, University of Michigan Rackham MERIT Fellowship to A.A, NIGMS grant (GM082856) to Y.D and NCI grant (CA250329) to Y.D and U-S.C.
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Contributed equally.